Tumor necrosis factor-α induces insulin resistance in endothelial cells via a p38 mitogen-activated protein kinase-dependent pathway
Tumor necrosis factor-α induces insulin resistance in endothelial cells via a p38 mitogen-activated protein kinase-dependent pathway
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DOI：
10.1210/en.2006-1441
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发表时间：
2007-07-01
期刊：
影响因子：
4.8
通讯作者：
Liu, Zhenqi
中科院分区：
文献类型：
--
作者：
Li, Guolian;Barrett, Eugene J.;Liu, Zhenqi
慢性炎症会导致血管胰岛素抵抗和内皮功能障碍。 TNF-α 的全身输注会消除胰岛素增强骨骼肌微血管灌注的作用。在骨骼肌中，TNF-α 通过 p38 MAPK 途径诱导胰岛素抵抗。为了检查 p38 MAPK 是否也调节 TNF-α 诱导的血管胰岛素抵抗，在血清饥饿 10 小时后，在存在或不存在 SB203580（p38 MAPK 特异性抑制剂，10 μM）的情况下，将牛主动脉内皮细胞 (bAEC) +/- TNF-α (5 ng/ml) 孵育 6 小时。最后 30 分钟，用 +/- 1 nM 胰岛素处理细胞，并测量胰岛素受体底物 (IRS)-1、Akt、内皮一氧化氮合酶 (eNOS)、p38 MAPK、ERK1/2、c-Jun N 末端激酶、AMP 激活蛋白激酶 (AMPK) 磷酸化和 eNOS 活性。 TNF-α 增加 p38 MAPK 磷酸化，有效刺激 IRS-1 丝氨酸磷酸化，并减弱胰岛素刺激的 IRS-1 酪氨酸和 Akt 磷酸化以及 eNOS 活性。 TNF-α 还有效刺激 ERK1/2 和 AMPK 的磷酸化。 SB203580 治疗可将 TNF-α 处理的 bAEC 中 p38 MAPK 磷酸化降低至基线，并恢复 IRS-1 酪氨酸和 Akt 磷酸化的胰岛素敏感性以及 eNOS 活性，而不影响 TNF-α 诱导的 ERK1/2 和 AMPK 磷酸化。我们得出的结论是，在培养的 bAEC 中，TNF-α 通过 p38 MAPK 依赖性机制诱导磷脂酰肌醇 3-激酶/Akt/eNOS 途径中的胰岛素抵抗，并增强独立于 p38 MAPK 途径的 ERK1/2 和 AMPK 磷酸化。 p38 MAPK 对 TNF-α 作用的这种差异调节表明，p38 MAPK 在 TNF α 介导的血管胰岛素抵抗中发挥关键作用，并可能导致 2 型糖尿病和心脏代谢综合征中出现的全身内皮功能障碍。
Chronic inflammation contributes to vascular insulin resistance and endothelial dysfunction. Systemic infusion of TNF-alpha abrogates insulin's action to enhance skeletal muscle microvascular perfusion. In skeletal muscle TNF-alpha induces insulin resistance via the p38 MAPK pathway. To examine whether p38 MAPK also regulates TNF-alpha-induced vascular insulin resistance, bovine aortic endothelial cells (bAECs) were incubated +/- TNF-alpha ( 5 ng/ml) for 6 h in the presence or absence of SB203580 ( p38 MAPK specific inhibitor, 10 mu M) after serum starvation for 10 h. For the last 30 min, cells were treated +/- 1 nM insulin, and insulin receptor substrate (IRS)-1, Akt, endothelial nitric oxide synthase ( eNOS), p38 MAPK, ERK1/2, c-Jun N-terminal kinase, and AMP-activated protein kinase (AMPK) phosphorylation, and eNOS activity were measured. TNF-alpha increased p38 MAPK phosphorylation, potently stimulated IRS-1 serine phosphorylation, and blunted insulin-stimulated IRS-1 tyrosine and Akt phosphorylation and eNOS activity. TNF-alpha also potently stimulated the phosphorylation of ERK1/2 and AMPK. Treatment with SB203580 decreased p38 MAPK phosphorylation back to the baseline and restored insulin sensitivity of IRS-1 tyrosine and Akt phosphorylation and eNOS activity in TNF-alpha-treated bAECs without affecting TNF-alpha-induced ERK1/2 and AMPK phosphorylation. We conclude that in cultured bAECs, TNF-alpha induces insulin resistance in the phosphatidylinositol 3-kinase/Akt/eNOS pathway via a p38 MAPK-dependent mechanism and enhances ERK1/2 and AMPK phosphorylation independent of the p38 MAPK pathway. This differential modulation of TNF-alpha's actions by p38 MAPK suggests that p38 MAPK plays a key role in TNF alpha-mediated vascular insulin resistance and may contribute to the generalized endothelial dysfunction seen in type 2 diabetes mellitus and the cardiometabolic syndrome.